2. Academic Validation
  3. Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production

Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production

  • J Med Chem. 2020 Sep 24;63(18):10433-10459. doi: 10.1021/acs.jmedchem.0c01086.
Xiaohui Du 1,  Jared Moore 1,  Brian R Blank 1,  John Eksterowicz 1,  Dena Sutimantanapi 1,  Natalie Yuen 1,  Todd Metzger 1,  Brenda Chan 1,  Tom Huang 1,  Xi Chen 1,  Yuping Chen 1,  Frank Duong 1,  Wayne Kong 1,  Jae H Chang 1,  Jessica Sun 1,  Tatiana Zavorotinskaya 1,  Qiuping Ye 1,  Melissa R Junttila 1,  Chudi Ndubaku 1,  Lori S Friedman 1,  Valeria R Fantin 1,  Daqing Sun 1
Affiliations

Affiliation

  • 1 ORIC Pharmaceuticals, 240 E. Grand Avenue, Floor 2, South San Francisco, California 94080, United States.
PMID: 32865411 DOI: 10.1021/acs.jmedchem.0c01086
Abstract

The adenosinergic pathway represents an attractive new therapeutic approach in Cancer Immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5'-(α,β-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 (35) proved to be a highly potent and orally bioavailable CD73 Inhibitor. In preclinical studies, 35 completely inhibited ADO production in both human Cancer cells and CD8+ T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.

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